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PubMed1992

Biodistribution of monoclonal antibody A7 and its F(ab')2 fragment in athymic nude mice bearing human pancreatic carcinoma.

Xenografts of a human pancreatic carcinoma cell line, HPC-YS, which reacted with the monoclonal antibody (MAb) A7, were used to investigate the in vivo localization of radioiodinated MAb A7 after intraperitoneal injection. MAb A7 localized to the tumor 4 days and 8 days after injection with a tissue/blood ratio of 1.45 +/- 0.18 and 2.04 +/- 0.20, respectively. The accumulation of MAb A7 in the tumor was 5%/g and 3.3%/g of the injected dose on day 4 and on day 8, respectively. In contrast, the F(ab')2 fragment of MAb A7 localized to the tumor 4 days after intravenous injection with a tissue/blood ratio of 14.2. The accumulation of the F(ab')2 fragment in the tumor was 1.2%/g of the injected dose. These results suggested that MAb A7 might be a suitable carrier of anticancer drugs for immunotargeting chemotherapy and that the F(ab')2 fragment might be potentially useful for the immunodetection of human pancreatic carcinomas.

Animals↗
PubMed1992

Gamma probe location of 111indium-labeled B72.3: an extension of immunoscintigraphy.

Eight colorectal and 5 ovarian cancer patients were evaluated with preoperative immunoscintigraphy and intraoperative gamma probe detection of 111indium-labeled monoclonal antibody B72.3. Immunoscintigraphy detected the presence of tumor in every patient shown to have tumor at surgery. There was one false-positive scan. A total of 21 pathologically verified lesions were identified at surgery in the 11 patients with tumor. Immunoscintigraphy localized 12 (57%) and intraoperative gamma probe detection located 17 (81%) of the lesions. Intraoperative probe detection located 6 of 8 lesions smaller than 1 cm and 3 lesions that were not identified on initial surgical exploration. The gamma probe offers information that is complementary to immunoscintigraphy in that (1) it aids the surgeon in locating intra- and extra-abdominal lesions previously identified by immunoscintigraphy, (2) it locates lesions too small to be seen by immunoscintigraphy alone, (3) it locates lesions that otherwise might be missed at surgery, and (4) it provides objective evidence for adequacy of surgical resection of cancer in the abdominal cavity.

Aged↗
PubMed1993

Increased tumor localization by monoclonal antibody A7 after F(ab')2 fragmentation in athymic nude mice bearing human pancreatic carcinomas.

Much recent research has been directed toward the use of monoclonal antibodies (MoAbs) for the immunodetection of solid tumors. In pancreatic cancer, conventional immunoscintigraphy using intact MoAbs remains disappointing. In this study, 125I-labeled F(ab')2 fragments produced by pepsin digestion of MoAb A7 were injected intravenously into nude mice bearing human pancreatic cancer, HPC-YS, xenografts that have previously been shown to react specifically with MoAb A7. The tumor tissue/blood ratio of 125I-labeled F(ab')2 fragments of MoAb A7 increased with time and was much higher than those for normal tissues. Moreover, the tumor tissue/blood ratio of 125I-labeled F(ab')2 fragments was greater than that of intact MoAb A7, although the F(ab')2 accumulation was less than that of intact MoAb A7 in the tumor. These results suggest that F(ab')2 fragments of MoAb A7 may be suitable carriers of radionuclides for immunodetection of human pancreatic cancer.

Animals↗
PubMedDate not supplied

Radioimmunoguided surgery in gastric cancer using 131-I labeled monoclonal antibody 3H11.

A clinical trial of radioimmunoguided surgery (RIGS) using 131-I labeled monoclonal antibody (MAb) 3H11 was performed on 25 cases with gastric cancer in this study. The results showed that the route of the administration of radiolabeled MAb is the key point of successful RIGS for gastric cancer. The RIGS in 19 cases in the group of submucosal injection via endoscope was very satisfying. For the detection of metastatic lymph nodes, the sensitivity rate of RIGS was 99.2% (118/119), the specificity, 97.7% (43/44), and the accuracy 98.8% (161/163). The accuracy rate in detecting tumor infiltration of the gastric wall was 95.9% (94/98), the sensitivity 94.6% (35/37), and the specificity 96.7% (59/61). Thus, the use of RIGS may improve the radical resectability rate and possibly the overall survival rate in patients with gastric cancer.

Adult↗
PubMed2002

Serotonin mediates CA1 spine density but is not crucial for ovarian steroid regulation of synaptic plasticity in the adult rat dorsal hippocampus.

The activity of the serotonin (5-hydroxytryptamine, 5-HT) system is sensitive to estradiol and progesterone. During the ovarian cycle, dendritic spines on CA1 pyramidal neurons of the dorsal hippocampus are increased by estradiol and later decreased by progesterone. We sought to determine whether 5-HT is involved in maintaining CA1 spine density and/or in steroid regulation of synaptic plasticity in dorsal hippocampus. Ovariectomized rats were treated (sc) over 10 days with the tryptophan hydroxylase inhibitor parachlorophenylalanine (pCPA) to deplete 5-HT, followed by estradiol benzoate on days 10 and 11. A subset of animals received progesterone on day 12. The day after the last treatment, rats were perfused and brains were processed for Golgi impregnation. Separate groups were processed for radioimmunocytochemistry (RICC) for the spine-associated protein, spinophilin, or high-performance liquid chromatography (HPLC) for monoamine analysis. Golgi and RICC data indicate that CA1 apical spine density was significantly decreased by pCPA (17-20%). Estradiol increased spine density in both saline- and pCPA-treated rats compared to respective controls (30%); however, pCPA animals maintained significantly fewer spines. No differences in spine densities were observed between saline- and pCPA-treated rats given estradiol and progesterone. Depletion of 5-HT by pCPA was confirmed in the CA1 (-90%) and dorsal raphe (-80%) by HPLC analysis. While 5-HT depletion was associated with a 57% decrease in CA1 norepinephrine (NE), there was no difference in dorsal raphe NE. Thus, whereas 5-HT is involved in maintaining spine density in the adult female rat CA1, it is not crucial for steroid-mediated plasticity. 5-HT-regulated spines/synapses may represent distinct populations from those modulated by estradiol and progesterone in dorsal hippocampus.

Animals↗
PubMed2002

A multiparameter screening assay to assess the cytokine-induced expression of endothelial cell adhesion molecules.

Compounds which inhibit endothelial cell inflammatory responses are believed to be of therapeutic value. The cell adhesion molecules E-selectin, ICAM-1, and VCAM-1 play important roles in inflammatory reactions by mediating leukocyte-endothelial interactions. To identify compounds which inhibit the expression of these adhesion molecules following cytokine stimulation we developed an assay which measures E-selectin, ICAM-1, and VCAM-1 in the same experiment. For this, we have taken advantage of the technology of time-resolved fluorimetry, which allows detection of several parameters in parallel, employing anti-E-selectin antibody labeled with europium, and anti-ICAM-1 and anti-VCAM-1 labeled with samarium and terbium, respectively. These antibodies were used to detect the respective antigens in human endothelial cells stimulated with TNFalpha or IL-1beta. In cross-competition assays these antibodies were found to bind specifically to TNF- or IL-1-stimulated cells. This assay, in which three parameters are measured in the same experiment, proved to be robust with signal to noise ratios of 25-35 for E-Selectin, 4-8 for ICAM-1, and 3-9 for VCAM-1. The assay proved to be reproducible in high-throughput screening. The experience with this assay demonstrates that multiple parameters can be measured in an enzyme-linked immunosorbent assay-type assay on cells by using time-resolved fluorimetry. The possibility of obtaining several parameters from one experiment is feasible under high-throughput screening conditions and is of interest for other experimental setups in which the simultaneous measurement of several parameters is desired.

Antibodies↗
PubMed1993

High-resolution positron emission tomography of human ovarian cancer in nude rats using 124I-labeled monoclonal antibodies.

PET has inherently high resolution and excellent contrast imaging and accurately measures radioactivity concentrations in vivo. When combined with specific immunological targeting it might provide a highly specific and sensitive radioimmunoscintigraphic tool. To investigate this we injected 124I-labeled MAb MX35 or MAb MH99 monoclonal antibodies (doses 200-400 mu Ci) intravenously into nude rats bearing subcutaneous human ovarian cancer xenografts (SK-OV-7 and SK-OV-3 cell lines). A melanoma cell line (SK-MEL-30) was used as a control tumor. These murine monoclonal antibodies react with cell-surface antigens expressed by most ovarian cancer cells, including the ovarian cell line used. Imaging was performed at 1-6 days using a high-resolution positron emission tomograph (PCR-I) with a spatial resolution of 4.5 mm. The slice thicknesses were 0.5 and 1.0 cm. Forty to seventy thousand coincident pulses were obtained per frame. The PET results were compared with those of autopsy and histology. Samples of blood, tumor, and normal tissues were obtained at various time points. PET calculation of isotope uptake ratios demonstrated specific localization of the antibodies in tumor, with ratios of tumor to normal tissue uptake as high as 6:1. Subcutaneous ovarian cancer nodules as small as 7 mm were identified with PET imaging. The results corresponded well with tissue sampling. Our findings suggest that PET imaging of tumors with 124I-labeled monoclonal antibodies may be useful in human diagnostic and therapeutic applications in ovarian cancer as well as other diseases.

Animals↗
PubMed1993

Clinical assessment of 111In-CYT-103 immunoscintigraphy in ovarian cancer.

The ability of 111In-CYT-103 immunoscintigraphy to aid in the diagnosis of patients with primary or recurrent/residual ovarian cancer was evaluated in a multicenter trial. The 111In-labeled immunoconjugate of the monoclonal antibody B72.3 was prepared using a site-specific conjugation method. A total of 103 patients received a 1 mg infusion of 111In-CYT-103 and subsequently underwent surgery or biopsy. The infusion of 111In-CYT-103 was well tolerated; only 1 patient experienced a modest elevation in blood pressure that was likely related to the infusion. 111In-CYT-103 immunoscintigraphy correctly identified surgically confirmed tumor in 68% of patients with ovarian adenocarcinoma. The sensitivity of 111In-CYT-103 immunoscintigraphy was positively influenced both by the size of the tumor lesion and the tumor TAG-72 antigen expression. The overall sensitivity of 111In-CYT-103 immunoscintigraphy was greater than that of CT imaging (44%). Antibody imaging detected occult disease in 20 of 71 patients with surgically documented ovarian adenocarcinoma; 6 patients being evaluated after initial surgery and chemotherapy had an otherwise negative presurgical workup and a normal CA 125 serum level. The results of this trial also indicate that 111In-CYT-103 immunoscintigraphy can contribute to the medical and surgical management of some patients with ovarian cancer. The results of this trial indicate that 111In-CYT-103 immunoscintigraphy should be a valuable addition to the presurgical evaluation of patients with suspected persistent or recurrent ovarian cancer.

Adenocarcinoma↗
PubMed1993

Biodistribution and intraoperative evaluation of radiolabeled monoclonal antibody MX35 in patients with epithelial ovarian cancer.

Murine monoclonal antibody (MAb) MX 35 shows strong homogeneous reactivity with more than 90% of epithelial ovarian cancers. Twenty-five patients with advanced ovarian cancer were entered into a clinical trial using 125I- or 131I-labeled MX 35 in doses of 2, 10, or 20 mg administered by intravenous (i.v.) or intraperitoneal injection. All patients underwent laparotomy at 7 to 20 days following MAb injection to assess tumor distribution, obtain biopsies of tumor and normal tissue, and evaluate the use of an intraoperative hand-held gamma-detecting device. Following i.v. injection, serum Mab half-life was 36 hr. Tumor biopsies obtained at surgery showed MAb accumulation of from 6.7 x 10(-3) to 4.0 x 10(-5)% injected dose/g of tissue. There was no correlation between absolute MAb accumulation in tumor and MAb dose administered. Regression analysis showed a correlation between MAb accumulation and the interval between MAb injection and surgery (P = 0.008). Specific localization of MAb in tumor was demonstrated by tumor:normal tissue ratios ranging from 2.3:1 to 34:1 (mean, 10.18:1). The tumor:normal tissue ratios were not significantly related to MAb dose, the level of immunohistochemical antigen expression, or the interval between MAb injection and surgery. Due to the relatively long serum half-life, mean tumor:serum ratios were only 1.53 following IV injection. This ratio did not correlate with MAb dose, days from injection, or antigen expression. There was an excellent correlation (P = 0.001) between MAb uptake, as measured by the intraoperative hand-held gamma counter, and direct gamma counting of excised tissues. MAb MX 35 localizes well to tumor in selected patients with ovarian cancer, and MAb uptake can be reliably quantitated in vivo with the hand-held intraoperative gamma counter.

Antibodies, Monoclonal↗
PubMed1994

Immunoliposomes and PEGylated immunoliposomes: possible use for targeted delivery of imaging agents.

Liposomes can be made target-specific by immobilizing antibodies on their surface against characteristic components of target organ or tissue. Possible schemes of antibody immobilization on liposomes are briefly considered. The use of immunoliposomes for the targeted delivery of diagnostic and therapeutic agents within the cardiovascular system is discussed. Immunoliposomes are shown to be suitable carriers for targeting blood vessel injuries, lung endothelium, and myocardial infarction. The role of polyethylene glycol in the preparation of long-circulation liposomes is investigated, and a hypothesis explaining the mechanism of polymer protective action in terms of physicochemical properties of diluted polymeric solutions is suggested. Polyethylene glycol-coated liposomes are investigated as possible carriers of imaging agents for gamma and MR visualization of different areas of interest in the body, including lymph nodes. The possibility of simultaneous immobilization of protective polymer and antibody on the liposome surface is proved, and the long-circulating targeted immunoliposomes are used for the targeted delivery of radiolabel to necrotic areas in rabbits with experimental myocardial infarction.

Animals↗
PubMed1996

Peritoneal carcinomatosis and radioimmunoguided surgery.

The Radioimmunoguided Surgery (RIGS) system was developed, in part, to detect occult tumor in patients with recurrent colorectal cancer. Unfortunately, however, patients are sometimes found to have unresectable peritoneal metastasis. For these patients, intraperitoneal hyperthermic perfusion (IPHP) with mitomycin C (MMC) was used as a novel treatment method. Thirty-six intraperitoneal hyperthermic perfusions with MMC were given over the course of several studies. A preliminary study delineated two groups as possible candidates for this treatment: patients with pseudomyxoma peritonei and patients with peritoneal metastasis < 0.5 cm. Intraperitoneal hyperthermic perfusion (IPHP) was conducted for 1 hour after achieving an abdominal temperature of 41 degrees C. A dose of 30 mg MMC in 31 Plasmalyte was injected followed by a second 30 mg dose given at 30 minutes. Plasma pharmacokinetics of IPHP with MMC indicate an advantage in the range of 100-fold enhancement of exposure compared with delivery in plasma. The method was found to be safe when flow was observed and dosage decisions were made during perfusion according to flow. A clinical study group consisting of 15 patients underwent cytoreductive surgery followed by IPHP. The majority of them had either gastrointestinal or urologic anastomoses. There were no complications. In every patient the CEA level decreased after surgery and IPHP, with a median response of 6 months. RIGS technology aided in the selection of IPHP as a treatment choice by demonstrating the presence of an occult tumor burden in those patients whose traditional explorations were deceiving. This chapter includes technical details and suggestions for improving and modifying the use of IPHP.

Antibiotics, Antineoplastic↗
PubMed1996

Radiology of peritoneal carcinomatosis.

In summary, the radologic appearance of peritoneal carcinomatosis and sarcomatosis is best understood with a thorough knowledge of the natural history of the disease. Computed tomography (CT) examinations of the abdomen and pelvis are insensitive to small volumes (< 5 cm) of diffuse peritoneal seeding. However, when larger volumes of peritoneal tumor are present, CT can be helpful defining the patients who are good candidates for complete cytoreduction (no small bowel disease) from those who are less likely to have a complete cytoreduction (extensive small bowel disease with clumping and obstruction). Thus CT examination plays a critical role in the identification of patients with mucinous tumors who are operative candidates. Further research is needed to improve sensitivity and in the monitoring of recurrence in patients with gastrointestinal cancer.

Humans↗
PubMed1996

Current status of staging laparotomy in colorectal and ovarian cancer.

Colon and rectal carcinomas. Accurate staging of colon and rectal carcinomas (CRCs) is vital to insure appropriate surgical and adjuvant therapy, and appropriate enrollment in and interpretation of adjuvant or neoadjuvant trials. Historically, CRC staging has relied on pathologic examination of surgical speciments. These newer techniques of endoscopic and intraoperative ultrasound, laparoscopy, and radioimmunoguided surgery may permit increased accuracy of staging by the surgeon. Cautious interpretation of investigations of these modalities is warranted, as studies include small numbers of patients and some of the work is preliminary. Despite this, we remain optimistic that as surgeons become more familiar with these techniques and as these modalities become more widely available, more accurate staging will facilitate optimal patient management in terms of complete resection of occult disease and appropriate adjuvant therapy. Ovarian carcinoma. The survival of patients with ovarian cancer has not appreciably changed in the past several decades. There are several reasons for this, some of which are related to the surgical procedures used to diagnose and treat these cancers. First, despite a great deal of literature that suggests an elevated CA-125 level in a postmenopausal woman with a pelvic mass is virtually diagnostic of ovarian carcinoma, an unexceptably large number of patients are still explored in community hospitals by a surgeon or obstetrician-gynecologist who is not prepared or adequately trained to perform the aggressive cytoreductive surgery that the patients require. Similarly, a large percentage of patients with "apparent" early ovarian cancer are not fully surgically staged at their initial surgery and often require reoperation to accurately define the extent of their disease, which will then determine the need for adjuvant therapy. Despite ongoing health care reforms, these patients should be referred to centers where the appropriate surgical procedure can be performed by an experienced gynecologic oncologist. Second-look laparotomy (SLL) has become more and more controversial, mainly because of a lack of effective second-line therapy, and should not be performed unless the patient fully understands its limitations and is willing preoperatively to participate in a subsequent trial based on the operative findings. Laparoscopy, both in the initial staging surgery and at reassessment laparotomy (SLL), is being re-evaluated but should be considered experimental until definitive trials determine its role.

Colorectal Neoplasms↗
PubMed1993

Imaging and dosimetry determinations using radiolabeled antibodies.

Numerous studies using radiolabeled antibodies for imaging and therapy of lymphoma have been reported (Table 4). The targeting of lymphoma associated antigens with MoAb appears to be more favorable than the targeting of antigens on epithelial tumor. Antigen abundance may not be the overriding factor in this favorable targeting, since the number of antigenic sites per cell are often in the same range or lower than those targeted in epithelial tumors. This improved targeting is likely related to the greater access of antibody to the target antigen in lymph nodes, bone marrow, circulation, and other sites. With certain antibodies, trafficking of the cells targeted with the radiolabeled antibody may also result in favorable localization [19]. While the most frequently used isotope for imaging and therapy has been 131I, certain limitations have been observed, including its high-energy gamma rays and resulting lower resolution, and the frequent occurrence of dehalogenation [21,25,98]. Many of the antigens expressed by lymphomas undergo antigenic modulation. Antigens that undergo modulation may be targeted successfully, but once modulation occurs the antibody is broken down and the iodine is rapidly excreted from the cells. While this rapid release from normal organs is an advantage, it is an undesirable event at the tumor site. In contrast to the case of 131I MoAb, modulation may be an advantage for targeting with 111In labeled antibodies, since the radioactive metals are retained for longer periods at the tumor sites; even if the antibody is broken down, the 111In is not easily excreted from the cells [52]. Among the most consistent and favorable targeting observed to date is that seen with 111In T101 in CTCL. These studies have shown concentration of 111In in tumor of 10-100 times that seen in other tumor systems using iodinated antibodies. Unfortunately no studies have followed this lead and performed the necessary comparisons between 111In and 131I MoAb to determine if this is a consistent finding. The use of 99mTc labeled MoAb for imaging lymphomas is in its infancy, although preliminary reports appear promising [71]. While in epithelial tumors preferential tumor targeting may take more than 48 hours in lymphomas, targeting is usually seen within the first 24 hours, which is within the window of imaging time for 99mTc. Therefore, further evaluation of 99mTc antibodies should be performed. Determination of the optimum dose of antibody for imaging has been attempted. Studies using various anti-lymphoma directed antibodies have shown widely varying biodistribution and variable dose-response curves.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗